Cardiovascular Risk in HIV Patients Switching From a Boosted Protease Inhibitor (PI) to Dolutegravir (DTG)

An Open Label Study Examining the Efficacy and Cardiovascular Risk of Immediate Versus Deferred Switch From a Boosted PI to Dolutegravir (DTG) in HIV Infected Patients With Stable Virological Suppression

The purpose of the study is to investigate the benefits of switching away from a kind of drug called a boosted protease inhibitor (PI) to a new drug called dolutegravir on patients' cardiovascular health (the health of their hearts). Patients are currently taking two other anti-HIV drugs, called nucleoside reverse transcriptase inhibitors (NRTIs), with their boosted PIs; these NRTIs will not be changed throughout the study. In order to compare the boosted PI and dolutegravir more accurately, half of study participants will be switched to dolutegravir immediately, and the other half will be switched after 48 weeks of continuing on the boosted PI.

Boosted PIs are associated with increased heart and circulation risk so it is hoped that switching from a boosted PI to dolutegravir will improve the health of the patients' hearts. Dolutegravir is a drug for HIV treatment which has been approved for use in HIV patients in the US and Europe. Clinical trials using dolutegravir have found that it is effective at suppressing the HIV virus, and it is at least as effective as the other drugs.

This study will also investigate the safety (in terms of other side effects and the routine blood tests which the investigators ordinarily use to monitor patients' treatment) and monitor effectiveness, patients' viral load and CD4 counts, when patients switch treatment from a boosted PI to dolutegravir. Viral load is the amount of the HIV virus they have in their blood, and CD4 count is a measure of a type of cell that is in their immune system. We also aim to improve patients' cardiovascular health in general by providing them with information on how to live a healthy lifestyle (eg improving their diet, stopping smoking etc).

Study Overview

• Status: Completed
• Conditions: HIV
• Intervention / Treatment: Drug: Dolutegravir

Detailed Description

Study Design: Randomised, non-inferiority strategic trial over 96 weeks with early or delayed switch from an ARV regimen containing a boosted PI plus 2 NRTIs to dolutegravir (DTG) plus 2 NRTIs in patients having achieved complete virological suppression for more than 24 weeks (HIV-1 RNA <50 c/ml). Patients will be randomised to switch at baseline or at 48 weeks.

Study visits will take place at screening, baseline, weeks 4 (immediate switch group only), 12, 24, 36, 48, 52 (deferred switch group only), 60, 72, 84 and 96, plus a follow up visit 28 days after the last dose of study medication.

Routine investigations will include viral load, CD4, haematology (including haemoglobin, white cell count and differential, platelets), biochemistry (including sodium, potassium, creatinine, albumin, glucose, ALT, ALP, total bilirubin, total cholesterol, HDL, LDL, triglycerides), quality of life questionnaires (EuroQL), urine sample (for haematuria, proteinuria, glycosuria, leukocytes, nitrate & pregnancy test in WOCBP)

• Study Type: Interventional
• Enrollment (Actual): 415
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Antwerp, Belgium, B-2000
    • Insititute Of Tropical Medicine Antwerp
  • Brussels, Belgium, 100
    • CHU Saint-Pierre
  • Gent, Belgium, 9000
    • Universitaire Ziekenhuis Gent
• France
  • Lyon, France, 69004
    • Hopital de La Croix Rousse
  • Nantes, France, 44093
    • Service des Maladies Infectieuses et Tropicales du CHU de NANTES
  • Paris, France, 75010
    • Hôpital Saint Louis
  • Paris, France, 75013
    • Pitie-Salpêtrière Hospital
  • Paris, France, 75018
    • Hospital Bichat Claude-Bernard
• Germany
  • Bonn, Germany, 53127
    • Universitatsklinikum Bonn
  • Essen, Germany, 45147
    • Universitatsklinikum Essen
  • Frankfurt, Germany, 60590
    • Klinikum der Goethe-Universität Frankfurt
  • Hamburg, Germany, 20146
    • ICH Infektiologisches Centrum Hamburg
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
• Italy
  • Firenze, Italy, 50011
    • Santa Maria Annunziata di Firenze
  • Milan, Italy, 20142
    • San Paolo Hospital
  • Milan, Italy, 20157
    • Azienda Ospedaliera - Polo Universitario 'Luigi Sacco'
  • Modena, Italy, 41124
    • Universitaria di Modena
• Spain
  • Alicante, Spain, 03203
    • Hospital General Universitario de Elche
  • Alicante, Spain, 03010
    • Universitario Alicante
  • Barcelona, Spain, 08025
    • Hospital de La Santa Creu I Sant Pau
  • Barcelona, Spain, 08036
    • Hospital Clínic Barcelona
  • Barcelona, Spain, 08907
    • Universitari de Bellvitge
  • Barcelona, Spain, 08916
    • IrsiCaixa
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Madrid, Spain, 28034
    • Hospital Ramón y Cajal
• United Kingdom
  • Brighton, United Kingdom, BN2 1ES
    • Elton John Centre
  • Bristol, United Kingdom, BS10 5NB
    • Southmead Hospital
  • London, United Kingdom, NW3 2QG
    • Royal Free Hospital
  • London, United Kingdom, W2 1NY
    • St Mary's Hospital
  • London, United Kingdom, SW10 9NH
    • Chelsea & Westminster Hospital
  • London, United Kingdom, SE1 7EH
    • St Thomas Hospital
  • London, United Kingdom, WC1E 6JB
    • Mortimer Market Centre
  • London, United Kingdom, E1 1BB
    • Bart's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient volunteers who meet all of the following criteria are eligible for this trial:

  1. Is male or female aged over 50, OR aged over 18 years with a Framingham risk score above 10%
  2. Has documented HIV-1 infection
  3. Has signed the Informed Consent Form voluntarily
  4. Is willing to comply with the protocol requirements
  5. Has been receiving an ARV regimen containing a boosted PI (darunavir, atazanavir, lopinavir, or fosamprenavir) plus 2NRTIs for >24 weeks
  6. Has stable virological suppression (plasma HIV-RNA <50 copies/mL for >24 weeks)
  7. If female and of childbearing potential, is using effective birth control methods and is willing to continue practising these birth control methods during the trial and for at least 2 weeks after the last dose of study medication. Note: Non-childbearing potential is defined as either post-menopausal (12 months of spontaneous amenorrhoea and ≥45 years) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy
  8. If a heterosexually active male, he is using effective birth control methods and is willing to continue practising these birth control methods during the trial and until follow-up visit

Exclusion Criteria:

• Patients meeting 1 or more of the following criteria cannot be selected:

  1. Infected with HIV-2
  2. Using any concomitant therapy disallowed as per the reference safety information and product labelling for the study drugs
  3. Has acute viral hepatitis including, but not limited to, A, B, or C
  4. Has chronic hepatitis B and/or C with AST and/or ALT >5 x ULN Note: Subjects can enter trial with chronic HBV if HBV-DNA undetectable at screen (and no detectable result in last 6 months) and with chronic HCV if not expected to require treatment during the trial period.
  5. Any investigational drug within 30 days prior to the trial drug administration
  6. History of exposure to any ARVs other than PIs or NRTIs except if switch was for tolerability/toxicity (NOTE: patients who have previously taken part in single drug trials for less than 14 days need not be excluded, or for virological failure with a genotypic resistance test without mutations
  7. Any prior evidence of primary viral resistance based on the presence of any major resistance-associated mutation to backbone NRTI
  8. History of prior virological failure,eg 2 consecutive HIV-1 RNA >50 c/ml -at or after week 32 following first ART initiation or confirmed rebound viraemia >200 copies/ml after having a VL of <50 copies/ml without resistance test or with significant mutations to any other ARV regimen (NOTE: Switch for toxicity or tolerability with wild type virus does not count as virological failure)
  9. Dialysis or renal insufficiency (creatinine clearance < 50ml/min)
  10. History of decompensated liver disease (AST or ALT≥5x the upper limit of normal (ULN) or ALT ≥ )3 x ULN and bilirubin ≥ 1.5 x ULN with > 35% direct bilirubin.
  11. Unstable liver disease (as defined by the presence of ascities, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), know biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones))
  12. Subjects with severe hepatic impairment (Class C) as determined by Child-Pugh classification
  13. If female, currently pregnant or breastfeeding
  14. Opportunistic infection within 4 weeks prior to first dose of DTG
  15. Clinical decision that a switch of antiretroviral therapy should be immediate
  16. Screening blood result with any grade 3/4 toxicity according to Division of AIDS (DAIDS) grading scale, except: asymptomatic grade 3 glucose, amylase or lipid elevation or asymptomatic grade 4 triglyceride elevation (re-test allowed).
  17. Any condition (including illicit drug use or alcohol abuse) or laboratory results which, in the investigator's opinion, interfere with assessments or completion of the trial.
  18. History or presence of allergy to the study drug or their components

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Immediate switch; Patients will be randomised to switch from a boosted PI to dolutegravir at baseline.	Drug: Dolutegravir; Dolutegravir 50mg once daily; Other Names: Tivicay
ACTIVE_COMPARATOR: Deferred switch; Patients will be randomised to switch from a boosted PI to dolutegravir after 48 weeks.	Drug: Dolutegravir; Dolutegravir 50mg once daily; Other Names: Tivicay

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Virological suppression	Maintenance of virological suppression (ie HIV-1 RNA <50 c/ml) after 48 weeks	48 weeks
Total cholesterol	Change from baseline in total cholesterol at week 48	48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Virological Suppression	Maintenance of virological suppression (ie HIV-1 RNA <50 c/ml) at week 24 and 96	24 - 96 weeks
CD4 count from baseline	Change in CD4 count from baseline to week 24, 48 and 96	24 - 96 weeks
Baseline in total cholesterol	Change from baseline in total cholesterol at weeks 24 and 96	24 - 96 weeks
Change from baseline to lipid values	Change from baseline to lipid values (LDL, HDL, triglycerides and TC:HDL ratio) and Framingham and DAD scores at weeks 24, 48 and 96	24 - 96 weeks
Safety	Safety (clinical and laboratory adverse events) at weeks 24, 48 and 96	24 - 96 weeks
Changes in markers of inflammation	Changes in markers of inflammation at baseline, week 48 and week 96	48 - 96 weeks
Tolerability	Tolerability (EuroQoL questionnaire) at weeks 24, 48 and 96	24 - 96 weeks
Changes in markers of coagulation	Changes in markers of coagulation at baseline, week 48 and week 96	48 - 96 weeks
Changes in markers of endothelial dysfunction	Changes in markers of endothelial dysfunction at baseline, week 48 and week 96	48 - 96 weeks
Change to arterial stiffness augmentation index at weeks 48 and 96	Change from baseline to arterial stiffness augmentation index at weeks 48 and 96	48 - 96 weeks
Change to average thickness of common carotid artery walls at weeks 48 and 96	Change from baseline to average thickness of common carotid artery walls at weeks 48 and 96	48 - 96 weeks

Collaborators and Investigators

• Sponsor: St Stephens Aids Trust
• Investigators: Principal Investigator: Jose Gatell, Dr, Spanish healthcare system

Publications and helpful links

General Publications

• Saumoy M, Sanchez-Quesada JL, Assoumou L, Gatell JM, Gonzalez-Cordon A, Guaraldi G, Domingo P, Giacomelli A, Connault J, Katlama C, Masia M, Ordonez-Llanos J, Pozniak A, Martinez E, Podzamczer D. Atherogenicity of low-density lipoproteins after switching from a protease inhibitor to dolutegravir: a substudy of the NEAT022 study. J Antimicrob Chemother. 2022 Jun 29;77(7):1980-1988. doi: 10.1093/jac/dkac117.
• Gatell JM, Assoumou L, Moyle G, Waters L, Johnson M, Domingo P, Fox J, Martinez E, Stellbrink HJ, Guaraldi G, Masia M, Gompels M, De Wit S, Florence E, Esser S, Raffi F, Stephan C, Rockstroh J, Giacomelli A, Vera J, Bernardino JI, Winston A, Saumoy M, Gras J, Katlama C, Pozniak AL; European Network for AIDS Treatment 022 (NEAT022) Study Group. Immediate Versus Deferred Switching From a Boosted Protease Inhibitor-based Regimen to a Dolutegravir-based Regimen in Virologically Suppressed Patients With High Cardiovascular Risk or Age >/=50 Years: Final 96-Week Results of the NEAT022 Study. Clin Infect Dis. 2019 Feb 1;68(4):597-606. doi: 10.1093/cid/ciy505.

Study record dates

Study Major Dates

• Study Start: April 1, 2014
• Primary Completion (ACTUAL): November 1, 2017
• Study Completion (ACTUAL): December 4, 2017

Study Registration Dates

• First Submitted: March 20, 2014
• First Submitted That Met QC Criteria: March 25, 2014
• First Posted (ESTIMATE): March 28, 2014

Study Record Updates

• Last Update Posted (ACTUAL): April 9, 2018
• Last Update Submitted That Met QC Criteria: April 6, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: HIV
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Dolutegravir
• Other Study ID Numbers: NEAT 22/SSAT 060

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED